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What Is the Reason for Lack of Translation in the Pain Field?

EDITOR'S NOTE: For this Inaugural Forum, Jeffrey Mogil of McGill University raises the question why have the fruits of basic research in the pain field not translated into new treatments? Read Jeff's introductory text and then share your opinion.

Despite greatly increased academic and industry resources aimed at basic, translational and clinical pain research over the past few decades, and despite an explosion in pain “targets” (my PainGenes Database currently lists 334 genes implicated causally in pain or analgesia based on null mutant studies alone), only a tiny handful of drugs acting at novel targets have been approved for use as analgesics. Why is this? It strikes me that there are at least five possibilities:

1. Non-predictivity of preclinical (animal) pain models: The “validity” of the models is not really the question, but rather their relevance. We all now seem to agree that the hot-plate test is probably of low relevance to human clinical pain. But what about chronic constriction injury (CCI), spared nerve injury (SNI), spinal nerve ligation (SNL), and complete Freund’s adjuvant inflammation (CFA)? Criticisms abound, involving either the assays themselves or the measures currently used within them (i.e., mechanical allodynia, heat hyperalgesia, and cold allodynia):

Human clinical pain lasts for years; measured changes in animal models often resolve in days or weeks.

Existing animal models are not etiologically valid. (CCI may be a decent model of causalgia, but causalgia is rare. Is it a useful model of post-herpetic neuralgia, or painful diabetic neuropathy?)

2. Species differences between rodents and humans: Is there a “right” model in animals at all?

Human pain biology is fundamentally different than rodent pain biology, even at "lower" levels. Drugs developed in the rat will therefore work in the rat, but not in humans.

Human pain biology is so much more complex than rodent pain biology, that drugs developed in rats don't make enough of a difference.

3. Failure of clinical trials to show efficacy: The failure of a clinical trial to show analgesic efficacy is either a failure of the drug (i.e., it’s not efficacious) or a failure of the trial. A number of recent negative Phase 3 trials of previously approved medications widely thought to be efficacious (and, of course previously shown to be efficacious in Phase 3 trials leading to their approval) have led some to wonder whether it is now more difficult to demonstrate analgesic benefit in a clinical trial than in the past. This could be for a number of reasons:

More and more clinical trials are being run by for-profit organizations than in the past, when they largely occurred in academic medical centers.

The overall number of clinical trials of analgesics is also increasing, such that more marginal analgesic compounds might be making it into trials.

Given the larger number of available analgesics now, patients willing to enroll in clinical trials might be more likely to be refractory to all treatments.

The larger number of available efficacious analgesics may be increasing the placebo response over time, making it harder to “beat” the placebo effect.

4. Barriers at the regulatory level: Is the “deck stacked against” analgesics at the FDA and EMEA?

Comments

Thank you for the opportunity to join this interesting new event. I read with interest Jeff's comments related to a key question for those working with pain: “What is the reason for lack of translation of basic information into new treatment?" I have one general and two specific comments.

General: The lack of translational fruits is an issue for chronic pain. When we talk about acute pain there has been clear improvement in our handling of these patients, e.g acute postoperative management. The problem is the long-lasting, often persistent pain.

There are two additional points I would like to make although Jeff has alluded to them:

1. The temporal aspect. The processing of pain is dynamic and extremely plastic under physiological and certainly in pathological conditions with different changes occurring over seconds, minutes, days, and probably years . This is rarely (if ever) taken into account. There needs to be correspondence between the experiments observed in animals and in humans. For example in clinical trials there is recruitment of patients that may have had their pain for 3-6 months in one end to patients that have had pain for several decades in the other end. Given the plasticity of the nervous system one can easily envision that the processing of pain is altered even if the underlying etiology (e.g. post-herpetic neuralgia) is the same. Just recently has the point about reproducibility in human pain conditions been taken up (Geber et al., 2011), but much more is needed.

2. Wrong and irrelevant measures. Measures in animals and humans are usually unidimensional. Predictivity to drug X is based on non-comparable responses in rodents and in humans. For example In rodents with a CCI the measure can be a spinal withdrawal response to a von Frey filament applied to the hind paw. Although efforts are taken to look at different responses they mostly rely on spinal reflex behavior. It is unlikely that such responses can reflect the experience of pain in a patient who has lost his job and his family because of a plexus avulsion.

In humans the pain measure is also often unidimensional but in another sense. The pain measure is often based on as simple intensity recording of a pain experience or relief of such. In these cases clinical scientists try to squeeze the complex pain experience into a simplistic measure where the multidimensional aspect of pain is reduced to one dimension. What about other biomarkers?

In his forum address, Jeff Mogil discusses several factors that may have contributed to a lack of translation from basic research to new pain treatments and asks for comments. As someone who spent a decade in the pharmaceutical industry in the area of early phase clinical trials of potentially new analgesic drugs, I would like to share my observations.

The pedigree of many compounds that have entered “proof-of-concept” clinical testing has been quite impressive. For example, compounds might have progressed to the clinic only if there was a high degree of selectivity for the target protein, the putative mechanism of action was defined and plausible for analgesia, pharmacokinetic (and sometimes functional) access to the CNS was confirmed, analgesic behavioral activity across multiple animal models and in multiple types of endpoints was demonstrated (often desired to be equal to or superior to “positive” controls known to be effective in at least one type of human pain condition). Yet the clinical failure rate has been extraordinarily high.

Do we get full value from animal models? The pharmaceutical industry has exploited animal models as a high throughput in vivo screen. The rush to progress compounds to the clinic overrides critically testing basic assumptions, such as causal evidence to support that the observed behavioral changes in the animal model directly relate to the putative mechanism of action of the compound under study. Avoidable, costly, premature or inappropriate clinical investments may be a symptom of the emphasis on speed and cost minimization at the preclinical stages (a false economy given the relative costs and timescales).

What constitutes a positive result in animal models? The declaration of an effect (statistical significance in mean change) may be insufficient for benchmarking an outcome of relevant or predictive value. We need to be more circumspect about which endpoints are important, the magnitude, completeness and duration of response normalization and the presence or absence of side effects.

What are effective or predictive doses? PK-PD modeling is based on ED50 (or EC50) estimates because this is relevant to comparative pharmacology methodology. But actual efficacy prediction and risk-benefit assessment may require exposure levels at ED95 or 3 to 5 x EC50. We just do not know if we are grossly underestimating target exposure.

Why are natural diseases in animals ignored? The very artificial nature of the models themselves may be a relevant issue. Natural diseases in animals provide access to abnormal nervous system tissues as well as potential pain models. A significant literature in pharmacological interventional trials in veterinary medicine demands more attention.

Who do we select for clinical trials? Negative clinical trial outcomes may have resulted from good studies in subjects with the wrong characteristics. A major difficulty in clinical trials for proof-of-efficacy is selecting the appropriate study population. Animal models have been poor at predicting what types of subjects to include or to exclude. Knowledge of a mechanism alone is insufficient. The results of the German Research Network on Neuropathic Pain indicate that most neurological abnormalities present across all types of neuropathic pain, suggesting that the common etiology-based approaches may be flawed. The choices made in selecting the study population and its characteristics may be crucial, but a meaningful basis to guide these choices a priori is lacking.

Is the effect size decreasing in clinical trials? Clinical trials are failing at the approval end as well. There are many possible reasons for this including a more “production line” approach to study site selection and to greater availability of approved therapies. However, the regulatory approval landscape has evolved significantly over the past decade, impacting the characteristics of acceptable clinical trial design and methodology of interpreting the results. Emphasis on analyses that account for trial non-completers and imputation methods that eliminate bias in the estimate of treatment effect and variance have a significant impact on the ability to design successful clinical trials, especially when the effect size is small. Changes in analysis methodology give the appearance of change in assay sensitivity.

Even a small improvement in the rate of translational success can make a huge difference to drug development efficiency. We need to be more circumspect about the animal models we use for decision making and how to interpret them.

Jeff’s question is good and the comments posted so far are quite insightful and I agree with the points made; however there are structural problems in the health care system and the way research is reviewed and funded that create barriers to successful translation. The single biggest problem is that most of the time we don’t know what’s wrong with patients with chronic pain. Because of this we don’t know whether any of animal models we use are valid or predictive. Why do we know so little about the patients? One reason is the vanishingly small group of physicians who both treat patients with chronic pain and understand the neurobiology of pain. The patients are complicated because of the unknown pain generating mechanism, the psychological responses to treatment failure and the possibility that certain medications can actually worsen pain. Unfortunately, there is no financial support for individuals who are willing to take the time to carefully and thoroughly examine patients. Without this it isn’t possible to determine all the factors that contribute to their pain complaint. Other than serendipity, the careful examination of patients in the context of a sophisticated understanding of the neurobiology of pain is a fountain from which advances come. How do we create the incentive for physicians to spend more time learning neuroscience and to spend more time examining their patients and reading the relevant literature? I have no idea how to do this and I can’t come up with a reasonable alternative.

Jeff and colleagues have made some very interesting and valid points about the translation of potential new targets from animal models to clinical pain models. I would like to add a couple of additional thoughts for consideration that extend many of the comments above.

1. Chronic pain is complex and involves multiple mechanisms and multiple diseases/syndromes. There are many chronic pain syndromes for which we likely have very different mechanisms: neuropathic pain/CRPS, arthritic pain, fibromyalgia. The likelihood that one target will be appropriate for all chronic pain syndromes is slim. As Howard Fields nicely points out, we do not really know what is wrong with these patients and therefore how can we validate an animal model. Each of these presents ina unique way in each individual pain syndrome. For example, CRPS is associated with cutaneous allodynia and spontaneous pain. On the other hand osteoarthritic patients have relatively low resting pain but significant pain during movement. Fibromyalgia patients have both pain at rest, and significantly increased pain with movement, as well as significant fatigue that can exacerbate the pain. The question we should keep in mind in our animal models is do we have the right tests for the individual pain syndrome?

2. The same type of reasoning ought ot be considered when designing clinical trials for pain. We have made incredible improvements in clinical trials in pain. If you go back to the early studies done just 20-30 years ago, many times the only measure was resting pain (VAS score). Clinical trials are now more inclusive and use a variety of survey data to examine pain, quality of life and impact of pain on function. I would suggest that we need to extend these trials to include pain during physical activity, tests of function, and impact on psychosocial variables. It could be that pain intensity ratings do not change but function, quality of life or impairments in psychosocial variables improve. I would contend that an effective "pain drug" could improve function and quality of life without having any effect on pain intensity.

I would like to submit that many new treatments, unless really stellar in terms of analgesic drug effect without adverse events, simply are not detected by anything but very large double-blind clinical trials.

Therefore, if the outcome of a new chemical entity depends upon positive outcome in a single well-controlled trial (rather than on outcome in several independent trials), an effective treatment has a very significant chance of being tossed out simply because of statistical noise.

Jeff made 5 good points and while others have also added extra issues to this complex debate, in my limited experience so far in the pain field (having come from a preclinical psychopharmacology background of about 15 years) I would have to say that the very first point he makes about the use of animals has had an extremely high impact. From recent work I have done it is clear to me that the end points are not entirely appropriate for studying response to pharmacology. The main reason is that the positive response in a reflex withdrawal assay (no matter what the stimulus) is a dampened response. This means that one cannot easily distinguish between a positive i.e. dampening effect and a motor impairing effect. I believe this has led to some inappropriate targets being advanced based on a side-effect. Assays that measure the normalisation of an ongoing behaviour would aid the field (in my humble opinion) e.g. the published work of Matson et al., 2007 using rearing activity (or my own "in review" work using the ethologically relevant behaviour burrowing). These potential importance of these types of assays is further enhanced since compounds such as ibuprofen and gabapentin are active at plasma concentrations that align with clinical plasma levels (unlike doses found active in the reflex withdrawal assays). I hope the debate continues in such a positive fashion.

Since most doctors refuse to obtain any education in pain care- and we know only 5 states require education in pain care as part of licensing- it should come as no surprise that there is lack of interest in translational research. Pain is not viewed as sexy by researchers as NIH blames lack of funding on pain research on the lack of interest in pain by researchers. Doctors, as Dr Leon Kass has indicated, don't seek to alleviate pain. They instead "hear the cries of suffering organs" when they wish to, but not the cries of people those organs happen to be attached to. With pain costing the nation in excess of $600 billion a year- and pain research at NIH not coming close to being 1% of that- who can deny that translational research -just like pain education is seen as uninmportant by modern medicine.

A question...Any idea why no-one ever used the King Charles Spaniel as a model for central neuropathic pain? In nearly all these dogs we can find a classical syringomyelia pain syndrome, the most elegant animal model for central neuropathic pain I know. Why does nobody use this? Just food for thought...

A deepening chasm separates the knowledge obtained from a physician touching a patient with persistent pain and the expression of this knowledge in an animal model.

This division exists since the translational medical models are emphasizing the movement of knowledge from the bench to bedside. However the transfer of knowledge from man to mouse has not occurred. By identifying the pathophysiology of persistent pain conditions in man, then the translation from man to mouse can begin. We can only translate the known.

As mentioned above, allowing the “natural disease” in animal models to occur will allow the development of abnormal nervous tissue that can be compared to the nervous tissue of humans who have the gradual onset of neuropathic pain. Then in-vivo biomarkers and in-vivo imaging can correlate man and mouse in pain studies.

The length of time pain behaviors persist in models is very important in neuropathic pain conditions, and is usually ignored in neural pain models. Most current neuropathic pain models have diminishing pain behaviors over 2-6 months, yet many human neural pain conditions can last years, with persistent or increasing pain behaviors. Many of the neuropathic pain models represent cell death or denervation as their pain behaviors wane … yet the changes seen in many patients may represent regeneration, not cell death.

One bit of evidence of the presence of regeneration in pain patients is the finding on physical examination of specific reflexes on the peripheral nerves that correlate to the neuroanatomy of the patient’s pain problem. These very specific reflexes may be related to the long studied “Pinch Reflex Test” (among others). This is a test with a tissue probe performed on sutured nerves and known to indicate with a reflex reaction the “site of regeneration”, with increased tenderness on the nerve below the “site” and decreased tenderness above.

Patients may have a site of dysfunction, inflammation or a conditioning lesion on a peripheral nerve resulting from an injury. This site over time can cause the gradual development of pain. Many physical therapists and some physicians can identify these lesions manually and then treat them, with resolution of pain. Diagnostic nerve blocks may be therapeutic in some.

In clinical experience gender, genetics, depression, stress, medications, activity and such will change the type of pain behaviors manifested, even in the same patient. These same factors can also influence the presence or absence of “spontaneous pain”.

The nerves are a forgotten soft tissue. The peripheral nerves are recognized to have a strong regenerative response to injury, even in rodents. A focus on healing and tissue repair after a soft tissue injury can provide more hopeful answers for sufferers of chronic pain, with more realistic biological targets.

Thanks for this opportunity. Such a forum can help practicing physicians begin to converse with basic scientists for a more hopeful future.